This year, a new and very special community formed at the EMBO Workshop ‘Developmental metabolism: flows of energy, matter, and information.’ Scientists from different disciplines including developmental biology, molecular metabolism, mathematics, and physics got the chance to exchange ideas. In addition, we had a brilliant poster session, where people got to vote for the best poster prizes resulting in one 1st place and four runners-up. Take a look!

1st place: Evolution of early embryonic energetics in animals

Presenter: Vinca Yadav, Max Planck Institute of Molecular Cell Biology and Genetics, Germany

Living systems continuously utilize energy to maintain their functions and stay alive. While doing so, they dissipate energy to their surroundings in the form of heat, as a result of metabolism. Embryos are particularly interesting systems from an energetic point of view, since most embryos rely on maternally preloaded nutrition to fuel their development, until they attain a feeding form. Given the diversity of embryonic developmental modes and the forms that they give rise to, we ask the question: how does embryonic energy requirement and metabolism vary in species with dramatically different developmental modes? We use isothermal calorimetry to measure heat dissipation rate – the classical definition of metabolic rate – as a readout of embryonic metabolism in species belonging to five evolutionarily distant groups. To compare our results effectively across species, we describe our measurements in terms of dynamic parameters during development such as cell number, plasma membrane content, and embryonic volume. We also employ a modelling-based approach to describe the rate of heat dissipation as a function of these parameters to try and understand potential commonalities in heat dissipation scaling of different groups. Our results reveal interesting patterns of energy dissipation across different groups, and suggest that heat dissipation may depend on embryonic volume, whereas the rate of dissipation might be correlated with the increasing cell plasma membrane area during very early development.

View poster (some parts of the poster have been blurred due to unpublished data)

The thermodynamic toolbox: understanding cellular metabolism quantitatively

Presenter: Václav Bocan, Max Planck Institute of Molecular Cell Biology and Genetics, Germany

During development, cells give raise to complex and cooperative structures and processes, such as the whole-body metabolism. Yet, cells maintain their own cellular metabolism in an out-of-equilibrium state independently by carefully calibrating the fluxes of mass and energy. Despite decades of research, we still do not have a quantitative understanding of how cells modify these fluxes under changing conditions while simultaneously adhering to the laws of thermodynamics. Our objective here is to develop a toolbox of general methods that can reveal the fundamental thermodynamic traits on a cellular scale to elucidate how cell energy budget is built.
To achieve this, we employ a combination of techniques to measure thermodynamic parameters in cultured mammalian cells. These methods include isothermal calorimetry (for metabolic heat dissipation), quantitative phase imaging (for cellular biomass growth), mass spectrometry (for nutrient consumption and waste secretion), and oxygen consumption rate analysis. By integrating these tools, we obtain a comprehensive view of cellular metabolism and deduce its global thermodynamic characteristics. Our ultimate goal is to describe metabolism using Gibbs free energy, which is the general driving force of all cellular metabolic processes.
We apply our toolbox to uncover how cells adjust their global bioenergetic state in response to varied conditions. We have already gathered heat and biomass growth rate data from several cell lines, including healthy-cancer tissue sample pairs from patients. Our analysis reveals significant differences in mass-specific heat dissipation, suggesting that the cancerous state profoundly impacts the thermodynamic tuning of metabolism. Our next steps involve investigation of the overall metabolic resilience, which we will probe by using inhibitors of key metabolic enzymes and changing nutrient availability (e. g. glucose and serum).
In summary, our methodology can quantitatively assess key thermodynamic parameters of cellular metabolism in varied physiological and experimental conditions, in a model- and pathway-independent manner. We plan to extend this approach to zebrafish embryos to elucidate how cellular metabolism reshapes throughout development.

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Synchronous metabolic and epigenetic reprogramming in secretory cells: a two-pronged regulatory mechanism

Presenter: Jonathan Briere, Institut de recherches cliniques de Montréal, Canada

Energy flux management is a cornerstone in cellular homeostasis and development. Pituitary secretory cells face a unique challenge due to their high hormone production rates. We have previously identified the cooperative role of two bZIP transcription factors, Creb3l2 and XBP1, in establishing robust secretory functions (Khetchoumian et al., Nat. Commun. 2019). These factors also induce a metabolic shift towards ATP production through oxidative phosphorylation over glycolysis. Intriguingly, the S6K1 kinase, a downstream effector of the mTORC1 pathway, augments protein synthesis and drives a metabolic shift toward glycolysis in cells expressing both Creb3l2 and XBP1. This coordination implies a connection between protein secretory functions and metabolic states, ultimately fine-tuning hormone production and secretion with energy metabolism.
To investigate this hypothesis, we carried out experiments using AtT-20 cells that express Creb3l2, XBP1, and/or S6K1. Transcriptomic analyses revealed a metabolic shift in cells expressing all three genes, including a two-fold increase in genes involved in glycolysis, glucose import, and lactate transport, a two-fold increase in mitochondrial Uncoupling protein genes, an eight-fold increase in beta-oxidation genes, and a two-fold increase in the glutathione pathway genes, all indicating a metabolic shift akin to the Warburg effect.
Endocrine cell populations exhibit inherent heterogeneity, a feature confirmed by our scRNA-seq data from mouse pituitary. The data unveiled an oscillatory metabolic shift among melanotrophs and corticotrophs subpopulations. These alternate subpopulations emphasize that energy metabolism is not uniform in all cells and shows that separate subpopulations have different activities, one predominantly producing, while the other secreting hormones.
Our data highlight the interdependence of metabolism and epigenetics. The input of nutrient availability and cell state acting through the S6K1 pathway on Creb3l2 and XBP1 genomic targets is crucial for cellular homeostasis, and its disruptions may lead to pathophysiological conditions. Ongoing in vivo studies will enhance our understanding of their impact on health and disease.

Poster not available due to unpublished data

The effect of maternal diet on offspring phenotypes

Presenter: Krittika Sudhakar, Van Andel Institute, United States of America

Parental diet influences the development of their offspring, while the prenatal environment such as the mother’s diet, stress, etc., can affect the adult phenotypes of the offspring. This is widely called the DOHaD hypothesis, which states that stress around pregnancy affects offspring development and health. These phenomena are rather interesting in fruit flies, Drosophila melanogaster because the female lay eggs and the eggs no longer have any contact with the mother during development. This infers that the effect of the parent’s environment is loaded in the egg itself and defines the offspring’s development and health later. In our study, we fed the females low, medium, and high-sugar diets for 10 days and mate them with males raised on control food. We assayed the phenotypes like body weight, lifespan, fecundity, triglycerides (TAG), etc., in the diet-fed mothers and their F1 offspring. The results of our preliminary studies show the effect of sugar diets on the mother’s fitness traits with decreased lifespan under low-sugar diets and increased TAG under high-sugar diets. Interestingly, the hatching time delay of ~2 h was observed in offspring from high-glucose-fed mothers, and the female offspring of both low and high-sugar-fed mothers show higher resistance to starvation as compared to a medium-sugar-fed control. We also further studied the metabolite profiling of the embryos from diet-fed mothers using the single-embryo RNA-sequencing and metabolomic methodology developed in our lab. Based on our results it is evident that offspring from nutrition-altered mothers might be metabolically challenged and have altered phenotypes themselves. 

Poster not available due to unpublished data

Upon ETC perturbations NAD levels limit the speed of the differentiation front in the fly eye

Presenter: Nisha Veits, Institut Pasteur, France

The various developmental decisions underlying the making of animals are temporally ordered and coordinated. Additionally, they occur at a stereotyped speed in a given species. How developmental speed is genetically encoded is poorly understood. Here, we use the developing Drosophila eye to investigate the molecular basis of developmental speed. The formation of the adult eye involves a differentiation front that sweeps through the eye imaginal disc to produce differentiated photoreceptor cells. While the regulatory logic underlying the progression of this differentiation front is well understood, how speed is regulated is not known. We report here on a tissue-specific RNAi assay that allows us to measure variations in the progression speed of the front independently of physiological cues acting at the organismal level. A small-scale screen of ~200 candidate genes identifies several genes involved in energy metabolism, including several components of the mitochondrial Electron Transport Chain (ETC). To better understand how these perturbations slow developmental speed, we are using fluorescent metabolic sensors, Mass Spectrometry Imaging and scRNAseq. Our first results indicate that the level of Nicotinamide Adenine Dinucleotide (NAD), an electron carrier acting as a cofactor in various metabolic pathways, becomes limiting for proper developmental speed upon perturbations in energy metabolism. 

Poster not available due to unpublished data

The EMBO Workshop ‘Developmental metabolism: flows of energy, matter, and information’ took place 12 – 15 September 2023 in EMBL Heidelberg and virtually.